The Th2-type immune response includes both innate and adaptive components that together can mediate immune protection against parasitic helminths. Elucidating the effector cell mechanisms directed against these parasites and identifying the regulatory cell populations that trigger their activation and differentiation remains at an early stage of understanding but may provide the basis for future vaccines and immune therapies. We have used the immune response to the intestinal nematode parasite, Heligmosomoides polygyrus, as a murine model to explore the role of memory T cells and innate effector cells in mediating worm expulsion. Our studies have shown that Th2 memory cells trigger the development of an immune cell infiltrate within several days after secondary inoculation, which includes alternatively activated macrophages. Furthermore, we showed that the macrophages mediate worm stress and expulsion through an arginase-dependent pathway. In this proposal, we will examine potential macrophage effector mechanisms, examining downstream events of arginine metabolism and other recently identified potential effector molecules associated with protective innate responses that are triggered by memory Th2 cells. We will also determine whether specific Th2 memory subsets are required to activate these macrophages, using an adoptive transfer system developed in the previous funding period. The short time interval in which memory T cells can induce a protective innate response makes the H. polygyrus system an especially compelling model. These studies will provide important insights into the requirements for Th2 memory cell development and function and the mechanism(s) through which innate cells, stimulated by Th2 memory cells, mediate host protective effects. PUBLIC HEALTH RELEVANCE: Helminth infection is a global health problem that also impacts susceptibility to other major infectious diseases. As yet, effective vaccines are not available, at least partly because of our limited knowledge of the components of the immune response that mediate protection. In the proposed studies we will examine immune mechanisms of protective immunity in a mouse model of intestinal nematode infection. We expect these studies to form the basis for the development of future immune therapies including novel vaccines.